Both authors contributed equally to the project.
Concise Total Synthesis of the Thiazolyl Peptide Antibiotic GE2270 A
Article first published online: 12 FEB 2008
Copyright © 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chemistry - A European Journal
Volume 14, Issue 8, pages 2322–2339, March 7, 2008
How to Cite
Delgado, O., Müller, H. Martin. and Bach, T. (2008), Concise Total Synthesis of the Thiazolyl Peptide Antibiotic GE2270 A. Chem. Eur. J., 14: 2322–2339. doi: 10.1002/chem.200701823
- Issue published online: 28 FEB 2008
- Article first published online: 12 FEB 2008
- Manuscript Received: 21 NOV 2007
- Deutsche Forschungsgemeinschaft. Grant Number: Ba 1372-9
- Alexander von Humboldt Foundation
- Universität Bayern e.V.
- natural products;
- total synthesis
The potent antibiotic thiazolylpeptide GE2270 A was synthesized starting from N-tert-butyloxycarbonyl protected valine in a longest linear sequence of 20 steps and with an overall yield of 4.8 %. Key strategy was the assembly of the 2,3,6-trisubstituted pyridine core by consecutive cross-coupling reactions starting from 2,6-dibromo-3-iodopyridine. The complete Southern fragment was installed by Negishi cross-coupling of 3-zincated 2,6-dibromopyridine at the terminal 2-iodothiazole of a trithiazole (87 %). The substituent at C-6 representing the Northern part of the molecule was introduced in form of the truncated tert-butyl 2-bromothiazole-4-carboxylate after metalation to a zinc reagent by another Negishi cross-coupling (48 %). Decisive step of the whole sequence was the macrocyclization to a 29-membered macrolactam, which was conducted as an intramolecular Stille cross-coupling occurring at C-2 of the pyridine core and providing the desired product in 75 % yield. The required stannane was obtained by amide bond formation (87 %) between a complex dithiazole fragment representing the Eastern part of GE2270 A and a 3,6-disubstituted 2-bromopyridine. Final steps included attachment of a serine-proline amide dipeptide to the Northern part of the molecule (65 %), formation of the oxazoline ring and silyl ether deprotection (55 % overall).